New Obesity Drug Could Have Fewer Side Effects

A novel compound called Lorcaserin helped overweight and obese people lose about 5 percent of their body weight, according to a study published today in the New England Journal of Medicine. While the weight reduction is modest, the drug could have fewer side effects than others that appear to be more effective.

The drug, developed by San Diego-based Arena Pharmaceuticals, acts on a specific subset of receptors for the chemical messenger serotonin. These receptors play a role in satiety, the feeling of fullness.

The company has been working to develop such a compound since the 1990s, when research linked appetite to some serotonin receptors in the brain. “This is the first tailor-made molecule to target receptors involved in producing satiety and reducing caloric intake,” says Arne Astrup, a physician at the University of Copenhagen, who wrote an editorial accompanying the paper in the NEJM. “I think we now have a much better understanding of the biology of these systems working in the brain and the peripheral effects than we did when some of the first compounds came on market. I think we feel more confident that this is a safe drug.”

Several weight-loss drugs have been pulled from the market or abandoned in late-stage development because of dangerous side effects. Long-term safety is a major concern, since previous studies suggest that in many cases such drugs must be taken continuously to maintain weight loss. “Weight-loss drugs only work as long as you take them,” says Steven Smith, a physician at Florida Hospital in Winter Park, FL, who led the study and is a paid consultant to Arena. “They are more like cholesterol or blood-pressure drugs than antibiotics, which cure an infection and can then be stopped.”

Lorcaserin was designed to target a subset of serotonin receptors called 5-HTC2. This specificity is in contrast to that of fenfluramine, a weight-loss drug often prescribed in the 1990s in combination with a second drug called phentermine (the combination was known as fen-phen). Fenfluramine was pulled off the market in 1997 after it was linked to heart-valve problems and pulmonary hypertension. These side effects were thought to come from the drug’s action on a set of serotonin receptors, 5-HT2B, found on heart and lung cells. By targeting brain receptors specifically, Lorcaserin appears to avoid these side effects.

In the new study, funded by Arena, scientists studied more than 3,000 people; half were given the drug, half took a placebo. After a year, approximately 55 percent of the drug group and 44 percent of the placebo group remained in the trial. Nearly 50 percent of the Lorcaserin group lost 5 percent of their body weight, compared to about 20 percent of the placebo group. About 20 percent of the drug group lost 10 percent of their body weight, compared to 7 percent of the placebo group. (Weight loss of about 10 percent is linked to decreases in cholesterol level and blood sugar.) Those who took the drug for a second year were more likely to maintain their weight loss; nearly 70 percent did so, compared to about half of those given a placebo in the second year.

The rate of weight loss with Lorcaserin is modest compared to other drugs in development, says Sajani Shah, an obesity expert at Tufts Medical Center, in Boston, who was not involved in the study. “But this drug looks more safe so far,” she says.

According to the study, the most common side effects were headaches, dizziness, and nausea. Most significantly, scientists did not see an increase in heart-valve disease in people who took Lorcaserin, though the researchers will need to show this is true in a larger number of patients in order to satisfy the U.S. Food and Drug Administration. The drug also appears to lack the psychiatric side effects, such as depression, seen with some other weight-loss drugs. Japanese drugmaker Eisai bought marketing rights to the drug on July 1.

Weight-loss drugs have had a troubled past. The field’s greatest recent hope, a drug called rimonabant, was pulled from the European market in 2007 due to an increased risk of depression and suicidal thinking. (It was not approved in the United States.) A second drug, called sibutramine, was withdrawn in Europe this year after being linked to an increased risk of stroke and heart attack. (The FDA plans to review the drug later this year.) And in May, the FDA warned that a drug called orlistat, sold over the counter as Alli, is linked to a rare type of liver injury.

Lorcaserin is one of three experimental weight-loss drugs the FDA will review this year, and the only novel compound in the group. The other two drugs, Qnexa and Contrave, are both combinations of existing drugs originally designed to target addiction, depression, and obesity. An FDA committee reviewed data on Qnexa, a combination of the weight-loss drug phentermine and the anticonvulsant topiramate, this week. A report released Tuesday concluded that the drug is effective but has some safety concerns. For example, clinical studies show it is linked to mild to moderate psychiatric side effects, such as depression.